Note: Descriptions are shown in the official language in which they were submitted.
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ORAL MEDICAMENT DELIVERY SYSTEM COMPRISING COLLAGEN-BASED FIBROUS MATRIX
Backctround of the Invention
I. Field of the Invention
The present invention relates to an oral medicament delivery system
and, in particular, to a fibrous composition for orally delivering a
medicament to
a patient.
I I. Description of the Prior Art
A common method of delivering a medicament to a patient is through
the oral cavity. Commonly utilized orally administrable formulations include
solid
formulations such as tablets, pills, capsules, oral dispersible pills,
dragees,
troches, lozenges and the like. However, administering medicaments via such
solid formulations presents challenges and drawbacks to a portion of the
patient populations. Statistically, at least 20 percent of the population
finds it
difficult to swallow solid oral medicament formulations and, consequently, are
averted to ingesting such formulations. Further, about 10 percent of women
are completely unable to swallow intact tablets, pills, and capsules, without
severing them into smaller pieces.
Patients are generally reluctant and/or averted to swallowing a solid
medicament formulation particularly when the act of swallowing is problematic
for the individual. Complications such as global hystericus and/or choking due
to pharyngeal and esophageal motility problems, generally render it painful
for
a patient to swallow. In addition, patients with pharyngitis and/or a markedly
swollen or an otherwise severely irritated pharynx, such as due to a bacterial
infection, often makes it difficult and/or impossible for the patient to
swallow.
Chronic disorders and other conditions, such as a psychological and/or
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psychosomatic aversion to the act of swallowing or a fear of choking on pills
and tablets, render patients even more reluctant to swallow solidly
formulated,
non-chewable medicaments. Patients may also be reluctant to swallow solid
medicament formulations due to their physical properties, including size,
shape,
and/or taste, or simply because of personal choice not to swallow and/or
ingest
the formulation.
Members of the pediatric patient population are reluctant to swallow
solid medicament formulations for additional reasons. Particularly, small
children generally dislike ingesting pills, tablets, and other "medicines." In
addition, children generally refuse to orally ingest a medication during
periods
of illness. Further, children are generally more inclined to chew pills and
tablets
than swallow them, typically experiencing a bitter taste in their mouths,
which
frequently causes children to either spit out or discard the formulation and
otherwise refuse to ingest it. Also, many of the available pills and tablets
are
scored in halves only and not in smaller portions, such as thirds or quarters,
thereby rendering dose titration of those pediatric medications difficult and
sometimes impossible. Accordingly, the child must swallow a larger porti4n of
those solid medications to obtain the physician directed and/or recommended
dose. Finally, it is even more difficult to co-administer a second solid
medicament formulation, which may be necessary to provide a specific benefit
such as to enhance the dose of the first medicament, to a child with a
physical
and/or mental aversion to swallowing a solid, non-chewable medication.
More recently, chewable and dissolvable forms of a medication have
been proposed. For example, U.S. Patent Nos. 4,855,326, 4,997,856,
5,034,42't, and 5,096,492, each disclose a floss-type melt-spun pharmaceutical
composition having a sugar-based carrier or a sugar-oleagenous combination
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carrier for delivering a medicament to a patient. However, due to physical
properties of the carrier materials, these compositions were found not to be
very stable for long periods of times. Particularly, being susceptible to the
degradative effects of humidity, such formulations have not been extremely
successful and/or extensively commercialized. More specifically, many
medicaments were found not to be stable with these carriers, thereby raising
the costs associated with that medication.
However, patients, whether a child or adult, under a medication
regimen and/or simply in need of the therapeutic benefits of a medicament
must be administered, or self-administer, the dosage formulation.
Thus, there is a need to provide a better method for orally
administering a medicament to a patient. There is a further need to orally
administer medicaments in a manner that addresses patient reluctance and/or
aversion to swallowing and/or ingesting a medicament formulation. There is a
further need to improve patient ingestion of a medicament in compliance with a
medication regimen, and in particular, improved compliance by pediatric
patients. There is yet a further need to provide a medicament formulation that
provides stability for a wide variety of medicaments.
Summary of the Invention
The present invention provides an oral medicament delivery system
comprising a fibrous pharmaceutical composition, for orally delivering a
medicament to a patient. The delivery system addresses weaknesses and
drawbacks associated with previously proposed oral medicament delivery
formulations and, in particular, addresses the drawbacks associated with
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previously proposed, and commonly utilized, solid medicament formulations.
Particularly, the delivery system addresses the problems associated with
swallowing pills, tablets, and other conventional solid medicament
formulations,
as described in the background section of the invention. In addition, the
delivery
system addresses the drawbacks associated with proposed sugar-based floss
as carriers for medicaments. Further, the pharmaceutical compositions, as part
of the delivery system, do not resemble a pill or tablet but have a fibrous
appearance and structure, microscopically, which renders the composition
mucous membrane adhesive, flexible and orally dissolvable and, therefore,
more acceptable and desirable to adult patients, and non-expectorable by
pediatric patients. Furthermore, this dose delivery form can be torn, cut or
severed with scissors to produce smaller dosage forms i.e., halves, quarters
or
other sizes).
The pharmaceutical composition in the oral medication delivery
system generally comprises a matrix formed of fibers, wherein some or all of
the fibers include a collagen-based carrier and a medicament. The fibrous
matrix is capable of partially or completely dissolving in the oral cavity to
deliver
a dose of the medicament, transmucosally or via the gut, to the patient. The
basic unit of the medicament-containing composition is a fiber, strand or
filament, as opposed to the micron-size particles and/or granules in
conventional pressure-compacted tablets.
The fiber in the composition is collagen-based, i.e., it is formed
primarily of collagen protein, and the medicament is incorporated therein or
distributed thereon in various embodiments. Thus, the collagen-based fiber
serves as a carrier or vehicle for delivering the medicament. Collagen
provides
many advantages as a carrier. Specifically, collagen has proven success in
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many bodily applications. Collagen is also capable of binding and carrying
charged active pharmaceutical ingredients (API). Collagen is relatively cheap,
readily available and its purity and sterility can be controlled. Collagen can
withstand aseptic processing techniques at mild temperatures ranging from
about 20°C to about 35°C, which many API's can withstand without
decomposition.
In embodiments of the invention, the medicament may be distributed
on, or incorporated in, each fiber, or a selected group of fibers, and may be
any
compound providing a biological and/or therapeutic benefit to the patient.
Thus,
exemplary medicaments include, without limitation, active pharmaceutical
ingredients (API), and non-actives such as vitamins, minerals and the like.
The
amount of the medicament is selected as desired, and generally depends upon
the particular medicament, accepted dosing practices for that medicament,
purpose of administration, and targeted patient population. The amount of the
medicament may also be dependant upon the amount, by weight, of the carrier
fiber and its inherent porosity and absorptive nature. Such dependency allows
the composition to be administered in a dose that can be titrated and/or
generally monitored, in accordance with the recommended dose.
In one embodiment, the composition, or the individual fibers, further
include excipients to provide desirable aesthetic, physical and/or chemical
properties to the orally administrable composition. For example, dissolvable
excipients including water-soluble substances including basic salts or
buffers,
which generally dissolve in saliva (mildly acidic) or in water-containing
fluids in
the oral cavity may be included in the composition. Simple sugars and
combinations thereof including mono-saccharides, di-saccharides and poly-
saccharides and other sweeteners generally provide a sweet taste, thereby
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rendering the composition further appealing to children. ~f aste masking
components may also be added to improve taste and/or to overcome offensive
bitter aftertastes from chewing and/or ingesting various broken or cut
tablets,
pills and capsules, which were otherwise intended to be swallowed.
Embodiments of the composition may also include a bio-adhesive or
muco-adhesive to adhere the composition to the patient's buccal mucous
membrane. Such adhesion allows the composition to be exposed for a period
of time, while retained on the oral mucous membrane, to appropriate
dissolution conditions, thereby dissolving the composition over time and
providing a delayed release effect for delivering the medicament to the
patient.
In addition, a muco-adhesive is advantageous for medicaments that are more
effective when absorbed across the mucosal membrane, thereby bypassing the
hepatic first pass effects.
The composition of the medicament delivery system is manufactured
using non-spun, non-melted methods, and is fibrous in nature, formed from a
flexible matrix of fibers. The matrix may be shaped into any suitable, or
desirable, form for oral ingestion. For example, the composition may exist in
a
coin-like circular shape the size of a dime or quarter. A "fusiform" shape is
also
contemplated, i.e., an elongate shape having a thick or broad central region
and thin terminal regions. Generally, most desired shapes may be prepared by
either (1 ) forming sheets of fibers, stacking multiple sheets one on top of
the
other to form layers, and then compacting and compressing these layers into a
unique shape, or (2) casting solutions of the matrix collagen material, with
or
without the medicament added, allowing the collagen to form a fibrous gel
matrix, then dehydrating, pressing, die-cutting, or otherwise processing the
gel.
The composition may also be marked to indicate a dosage time and/or
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schedule, and/or perforated or scored to allow the composition to be easily
severed.
The fibrous nature of the composition provides advantages over
conventional pills, tablets, capsules, oral dispersal forms (i.e. "melting
tablets")
and other solid oral dosage formulations. Particularly, it allows the
composition
to be easily cut and severed, unlike most conventional tablets, pills and
capsules. This benefit provides the ability to titrate and/or monitor the dose
administered to the patient. The chewable and dissolvable nature of the
composition render it more likely to be ingested by pediatric patients, who
may
otherwise be physiologically and/or psychologically reluctant to swallow a
conventional solid dosage formulation. Further, in accordance with another
aspect of the invention, the flexibility of the fibrous matrix allows the
composition to be wrapped around other dosage formulations, such pills and
tablets, for co-administration of multiple medicaments to a patient. For
example, the fibrous matrix contains one or more API's while a pill or tablet
or
other dosage wrapped therein includes other different API's. Alternatively,
the
fibrous matrix includes an API for rapid delivery and a solid dosage wrapped
therein includes the same or similar API for more delayed release. In another
embodiment, compositions having mucoadhesive properties also prevent the
pediatric patient, non-compliant patient, and/or obstreperous patient from
spitting the composition out of their mouths. In addition, unlike oral
dispersible
tablets, such as Zydis~ formulations and others, the present fibrous
composition is not API dose limited.
The present invention also provides methods of forming the fibrous
medicament-containing composition and methods for administering it to a
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patient. The composition may be administered directly, by placing it in the
patient's oral cavity, or indirectly by, for example, first suspending or
dissolving
it in an amount of a liquid, such as water, juice or other patient selected
beverage, in a spoon, glass, cup or other vessel of choice. In either method,
the
composition dissolves and disperses the medicament in the liquid (or saliva)
prior to ingestion by the patient. Conventional pills and tablets generally do
not
dissolve in saliva or a chosen liquid. Accordingly, the oral medicament
delivery
system of the present invention encourages ingestion of a medicament, in
compliance with a medication regimen. Particularly, the composition in liquid
form is easily swallowed and is generally not thereafter retained and later
expelled from the mouth. In this manner, the present invention also improves
compliance in psychiatric and/or other non-compliant patients.
Brief Description of the Drawings
The accompanying drawings, which are incorporated in and
constitute a part of this specification, illustrate embodiments of the
invention
and, together with a general description of the invention given above, and the
detailed description of the embodiments given below, serve to explain the
principles of the invention.
Figure 1 is one exemplary form of the pharmaceutical composition in
the present invention;
Figure 2 is a second exemplary form of the pharmaceutical
composition in the present invention;
Figures 3A-3F illustrate a first exemplary method of making the
medicament-containing, collagen-based composition of the present invention;
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Figure 4 is a perspective, exploded view of the product made by the
exemplary method illustrated in Figures 3A-3F;
Figure 5 is a perspective view the compressed product made by the
exemplary method illustrated in Figures 3A-3F;
Figure 6 illustrates a second exemplary method 'of making the
medicament-containing, collagen-based composition of the present invention;
and
Figure 7 is a partial cut-away view of the product made by the
exemplary method illustrated in Figure 6.
Detailed Description of Exemplary Embodiments
The present invention will be further appreciated in view of the
following definitions:
The term "system" with respect to delivery of a medicament, is
generally intended to refer to one or more compositions delivered to the
patient.
Thus, this term contemplates delivery of a single pharmaceutical composition,
such as the fibrous composition alone, or a combination of pharmaceutical
formulations, such as the fibrous composition with one or more other
formulations, administered simultaneously or sequentially one after another.
The term ''matrix", as used herein, is intended to generally refer to a
weave or web of fibers, strands, threads or filament-like structures. For
example, the fibers may be inter-woven, cross-woven, or arranged in any other
orientation relative one another to form a matrix, as appreciated by one of
ordinary skill in the art.
- 25 The term "collagen-based", as used herein with reference to the
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composition of the carrier, is intended to generally refer to a material that
is
primarily comprised of a form of collagen. Thus, this term contemplates 100%
collagen carrier, and also carriers having at least 50% by weight of a
collagen
material. This term also contemplates all forms of collagen, natural or
synthetic,
including homo-polymers, cross-linked polymers (tropocollagen), copolymers
and strands of collagen, as well as collagen-type proteins. Accordingly, this
term also encompasses chemically modified collagen, formed by known
synthetic methods such as by replacing one or more of the amino acids in the
collagen protein backbone, or modifying the side chains of the polymer(s).
The term "carrier", as used herein, is intended to generally refer to a
vehicle or substrate for delivering the medicament to~the patient.
The term "medicament", as used herein, is intended to generally refer
to any biological substance having a physiological and/or therapeutic effect
on
a patient. For example, the term "medicament" encompasses all active
pharmaceutical ingredients (API), non-active ingredients including vitamins,
minerals, dietary components, and the like. This term also encompasses
compounds, which are administered for their therapeutic and/or prophylactic
effects.
The terms "orally dissolvable" and "orally dispersible", as used herein
with reference to the composition, is intended to generally refer to the
breakdown, up to and including complete dissolution, of the composition. Thus,
this term encompasses compositions, which partially or fully breakdown or
dissolve in a particular medium, such as saliva, or aqueous liquids and foods,
present in the oral cavity. As such, this term encompasses all compositions,
which will generally dissolve in the oral environment stimulated with liquid
or
other substance to generate the secretion of saliva.
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The present invention provides an oral medicament delivery system
comprising a fibrous pharmaceutical composition, and also provides methods
for orally delivering a medication to a patient. The pharmaceutical
composition
is generally a fibrous matrix formed of a plurality of fibers. The composition
is
sufficiently dissolvable in the oral cavity to deliver a unit dose of the
medicament to the oral mucosal membrane, or the gut via ingestion, of the
patient.
Each fiber may generally serve as a carrier to deliver the one or more
medicaments to the patient's oral cavity. The carrier is generally formed of
collagen or a collagen-based material. Collagen is a naturally occurring
fibrous
protein formed of fibers having a high tensile strength, and whose solubility
in
aqueous and organic media, such as alcohol and ether, varies depending upon
the particular structure and form of the collagen. Collagen provides many
advantages as a carrier. Particularly, collagen has been successful in
physiological applications and uses, including use as implants and hemostatic
agents in the medical industry, as topical agents in the cosmetic industry,
and
as ingestible products in the food industry. Collagen may possibly be charged
thereby enhancing its binding and/or carrying capability for charged
medicaments, and particularly charged active pharmaceutical ingredients (API).
Collagen is relatively cheap and readily available in a multitude of sources
and
raw materials and, therefore, provides a low cost base material, relative to
many other formulation materials. In addition, the purity of the collagen can
be
controlled.
Further, the processing of collagen lends itself to pharmaceutical
formulation by withstanding aseptic techniques and by being readily processed
at mild temperatures ranging from about 20°C to about 35°C. Such
ambient
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temperature allows for the inclusion of many API's without the risk ofi
degradation and/or chemical decomposition, which may otherwise result from
exposure to higher temperatures. Also, collagen is a suitable extrusion
candidate for the medicament carrier material. Once in solution, collagen can
easily be strained of its solvent liquid and extruded to form rapidly drying
and
solidifying fibrous strands or threads. Alternatively, collagen in solution
may be
induced to form a fibrous gel matrix by a process called reconstitution. These
gels may be further processed to yield non-woven fibrous matrices having a
highly porous structure.
Moreover, the physical properties of collagen are desirable.
Specifically, many forms of collagen are hydroscopic and, therefore, soluble
in
saliva and most other fluids, and foods, typically present in the oral cavity.
The
mechanical and chemical properties of collagen matrices can be varied during
processing to control their handling and dissolution properties. This can be
accomplished by such means as using various salts, acids or enzymes during
the original collagen extraction process, by modifying the extrusion of gel
reconstitution process, or by using cross-linking agents or other treatment
methods during production of the collagen matrix. Thus, collagen or a
collagen-based material as the carrier provides many properties particularly
useful for an orally administrable medicament formulation.
The amount of collagen in each strand of fiber may vary depending
on the desired properties of the administrable composition. For example, being
hygroscopic, highly porous, and generally soluble in aqueous-based liquids,
including saliva, large amounts of the collagen-based carrier are not
necessary.
The amount of collagen may also be based upon the amount of the
medicaments) carried within or distributed on the fiber, as is discussed
herein.
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The medicament associated with the fiber, and the composition as a
whole, may be selected as desired. Suitable medicaments include active
pharmaceutical ingredients (API). For example, the medicament may be any of
the following API's, many of which are well-known drugs:
Analgesic anti-inflammatory agents, such as acetaminophen, aspirin,
salicylic acid, methyl salicylate, choline salicylate, glycol salicylate, 1-
menthol,
camphor, mefenamic acid, fluphenamic acid, indomethacin, diclofenac,
alclofenac, ibuprofen, ketoprofen, naproxene, pranoprofen, fenoprofen,
sulindac, fenbufen, clidanac, flurbiprofen, indoprofen, protizidic acid,
fentiazac,
tolmetin, tiaprofenic acid, bendazac, bufexamac, piroxicam, phenylbutazone,
oxyphenbutazone, clofezone, pentazocine, mepirizole, and the like;
Drugs having an action on the central nervous system, for example
sedative agents, hypnotic agents, anti-anxiolytic agents, analgesic and
anesthetic agents, such as chloral, buprenorphine, naloxone, haloperidol,
fluphenazine, pentobarbital, phenobarbital, secobarbital, amobarbital,
cydobarbital, codeine, lidocaine, tetracaine, dyclonine, dibucaine, cocaine,
procaine, mepivacaine, bupivacaine, etidoca.ine, prilocaine, benzocaine,
fentanyl, nicotine, morphine, codeine, hydrocodone, hydromorphone,
diacetylmorphine, methadone, sufentanyl, meperidine, levodromoran, and the
like;
Antihistaminic or anti-allergenic agents such as, diphenhydramine,
dimenhydrinate, perphenazine, triprolidine, pyrilamine, chlorcyclizine,
promethazine, carbinoxamine, tripelennamine, brompheniramine, hydroxyzine,
cyclizine, meclizine, clorprenaline, terfenadine, chlorpheniramine,
phenylpropanolamine, phenylephrine, atropine, hyoscyamine, cyproheptidine,
and the like;
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Anti-inflammatory agents including steroids, such as hydrocortisone,
cortisone, dexamethasone, fluocinolone, triamcinolone, medrysone,
prednisolone, flurandrenolide, prednisone, halcinonide, methylprednisolone,
fludrocortisone, corticosterone, paramethasone, betamethasone, ibuprophen,
naproxen, fenoprofen, fenbufen, flurbiprofen, indoprofen, ketoprofen,
suprofen,
indomethacin, piroxicam, aspirin, salicylic acid, diflunisal, methyl
salicylate,
phenylbutazone, sulindac, mefenamic acid, meclofenamate sodium, tolmetin,
androgenic steroids, such as, testosterone, methyltestosterone,
fluoxymesterone, estrogens such as, conjugated estrogens, esterified
estrogens, estropipate, 17-beta estradiol, 17-beta estradiol valerate,
equilin,
mestranol, estrone, estriol, 17-beta ethinyl estradiol, and
diethylstilbestrol;
progestational agents such as progesterone, 19-norprogesterone,
norethindrone, norethindrone acetate, melengestrol, chlormadinone,
ethisterone, medroxyprogesterone acetate, hydroxyprogesterone caproate,
ethynodiol diacetate, norethynodrel, 17-alpha hydroxyprogesterone,
dydrogesterone, dimethisterone, ethinylestrenol, norgestrel, demegestone,
promegestone, megestrol acetate, and the like;
Respiratory agents such as theophilline and beta2 -adrenergic
agonists such as albuterol, terbutaline, metaproterenol, ritodrine,
carbuterol,
fenoterol, quinterenol, rimiterol, solmefamol, soterenol, tetroquinol,
caffeine,
caffeine citrate, and the like;
Sympathomimetic agents, such as dopamine, norepinephrine,
phenylpropanolamine, phenylephrine, pseudoephedrine, amphetamine,
propylhexedrine, arecoline, and the like;
Local anesthetics agents, such as benzocaine, prilocaine,
bupivocaine, procaine, dibucaine, lidocaine, and the like;
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Antimicrobial agents including antibacterial agents, antifungal agents,
antimycotic agents and antiviral agents; tetracyclines such as,
oxytetracycline;
penicillins such as a mpicillin; cephalosporins such as cefalotin;
aminoglycosides such as kanamycin; macrolides such as erythromycin,
chloramphenicol, iodides, nitrofrantoin, nystatin, amphotericin, fradiomycin,
sulfonamides, purro(nitrin, clotrimazole, miconazole chloramphenicol,
sulfacetamide, sulfa rnethazine, sulfadiazine, sulfamerazine, sulfamethizole
and
sulfisoxazole; antivirals, including idoxuridine; clarithromycin; and other
anti-
infectives including nitrofurazone, and the like;
Antihypertensive agents such as clonidine, alpha-methyldopa,
reserpine, syrosingopine, rescinnamine, cinnarizine, hydrazine, prazosin, ACE
inhibitors, propanolol, pindolol, labetalol, clonidine, captopril, enalapril,
lisonopril, and the like;
Antihypertensive diuretics such as chlorothiazide,
hydrochlorothrazide, bendoflumethazide, trichlormethiazide, furosemide,
tripamide, methylclothiazide, penfluzide, hydrothiazide, spironolactone,
metolazone, and the like;
Cardiotonic agents such as digitalis, ubidecarenone, dopamine, and
the like;
Coronary vasodilators such as organic nitrates including, without
limitation, nitroglycerine, isosorbitol dinitrate, erythritol tetranitrate,
pentaerythritol tetranitrate, dipyridamole, dilazep, trapidil, trimetazidine,
and the
like;
Vasoconstrictors, such as dihydroergotamine, dihydroergotoxine, and
the like;
Beta-blockers or antiarrhythmic agents, such as timolol pindolol,
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propranolol, and the like;
Calcium antagonists and other circulatory organ agents including,
without limitation, aptopril, diltiazem, nifedipine, nicardipine, verapamil,
bencyclane, ifenprodil tartarate, molsidomine, clonidine, prazosin, and the
like;
Anti-convulsive agents such as nitrazepam, meprobamate,
phenobarbitol, carbomazepine, valproic acid, oxazepine, phenytoin, and the
like;
Agents for dizziness and nausea such as isoprenaline, betahistine,
scopolamine, and the like;
Tranquilizing agents such as reserprine and chlorpromazine; and
antianxiety benzodiazepines, such as alprazolam, chlordiazepoxide,
clorazeptate, halazepam, oxazepam, prazepam, clonazepam, flurazepam,
triazolam, lorazepam, diazepam, and the like;
Antipsychotic agents such as butyrophenones and phenothiazines
including, without limitation, thiopropazate, chlorpromazine, triflupromazine,
mesoridazine, piperracetazine, thioridazine, acetophenazine, fluphenazine,
perphenazine, trifluoperazine, and other major tranqulizers such as
chlorprathixene, thiothixene, haloperidol, bromperidol, loxapine, and
molindone,
as well as those agents used at lower doses in the treatment of nausea,
vomiting, and the like;
Muscle relaxants, such as tolperisone, baclofen, dantrolene sodium,
cyclobenzaprine, and the like;
Drugs for Parkinson's disease, spasticity and acute muscle spasms,
such as levodopa, carbidopa, amantadine, apomorphine, bromocriptine,
selegiline (deprenyl), trihexyphenidyl hydrochloride, benztropine mesylate,
procyclidine hydrochloride, baclofen, diazepam, dantrolene, and the like;
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Respiratory agents and cough suppressants such as codeine,
ephedrine, isoproterenol, dextromethorphan, orciprenaline, ipratropium
bromide, cromglycic acid, and the like;
Non-steroidal hormones or antihormones such as corticotropin,
oxytocin, vasopressin, salivary hormone, thyroid hormone, adrenal hormone,
kallikrein, insulin, oxendolone, and the like;
Antitumor agents such as 5-fluorouracil and derivatives thereof,
krestin, picibanil, ancitabine, cytarabine, and the like;
Enzymes such as lysozyme, urokinaze, and the like;
Herb medicines or crude extracts such as glycyrrhiza, aloe, Sikon
(Lithospermi Radix), and the like;
Miotic agents such as pilocarpine, and the like;
Cholinergic agonists such as choline, acetylcholine, methacholine,
carbachol, bethanechol, pilocarpine, muscarine, arecoline, and the like;
Antimuscarinic or muscarinic cholinergic blocking agents such as
atropine, scopolamine, homatropine, methscopolamine, homatropine
methylbromide, methantheline, cyclopentolate, tropicamide, propantheline,
anisotropine, dicyclomine, eucatropine, and the like;
Mydriatic agents such as atropine, cyclopentolate, homatropine,
scopolamine, tropicamide, eucatropine, hydroxyamphetamine, and the like;
Psychic energizers such as 3-(2-aminopropy)indole, 3-(2-
aminobutyl)indole, and the like;
Humoral agents such as the prostaglandins, natural and synthetic, for
example, PGE~, PGE~alpha, and PGF2alpha., and the PGE~ analog
- misoprostol.
Antispasmodic agents such as atropine, methantheline, papaverine,
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cinnamedrine, methylscopolamine, and the like;
Antidepressive agents such as isocarboxazid, phenelzine,
tranylcypromine, imipramine, amitriptyline, trimipramine, doxepin,
desipramine,
nortriptyline, protriptyline, amoxapine, maprotiline, trazodone, and the like;
Anti-diabetic agents such as insulin, and anticancer drugs such as,
tamoxifen, methotrexate, and the like;
Anorectic drugs such as dextroamphetamine, methamphetamine,
phenylpropanolamine, fenfluramine, diethylpropion, mazindol, phentermine,
and the like;
Anti-allergenic agents such as antazoline, methapyrilene,
chforpheniramine, pyrilamine, pheniramine, and the like;
Decongestants such as phenylephrine, ephedrine, naphazoline,
tetrahydrozoline, and the like;
Antipyretic agents such as aspirin, salicylamide, and the like;
Antimigrane agents such as dihydroergotamine, pizotyline, triptans,
and the tike;
Anti-malarial agents such as the 4-aminoquinolines,
alphaaminoquinolines, chloroquine, pyrimethamine, and the like;
Anti-ulcerative agents such as misoprostol, omeprazole, enprostil,
and the like;
Peptides such as growth releasing factor, and the like;
Anti-estrogen or anti-hormone agents, such as tamoxifen or human
chorionic gonadotropin, and the like; and
Antiulcer agents such as allantoin, aldioxa, alcloxa,
methylscopolamine methylsuflate, and the like.
The exemplary medicaments and drugs listed above may be used
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individually or in combination as required. Moreover, the drugs may be used
either in their free-base form or, if capable of forming salts, in the form of
a salt
with a suitable counter ion, such as a suitable acid or base. Suitable acidic
counter ions include, without limitation, organic acids such as methane
sulfonic
acid, toluene sulfonic acid, lactic acid, tartaric acid, fumaric acid, malefic
acid,
succinic acid, acetic acid and the like, and inorganic acids, such as
hydrochloric
acid, hydrobromic acid, hydrofluoric acid, phosphoric acid, sulfuric acid and
the
like. Suitable basic counter ions include, without limitation, organic bases
such
alkyl amines including triethylamine, and the like, and inorganic bases, such
as
sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide,
ammonia and the like. If the medicament has a carboxylic acid functional
group, then derivatives of the acid, such as an ester, an anhydride or an
amide,
may be employed. The esters may include alkyl esters, aryl esters, aralkyl
esters, and the like, and may also have functional groups capable of
themselves forming salts.
The medicament may also be a nutritional ingredient such as a
vitamin, mineral, and the like. The term "vitamin", as used herein, includes,
without limitation, thiamin, riboflavin, nicotinic acid, pantothenic acid,
pyridoxine,
biotin, folic acid, vitamin B6, vitamin B~2, lipoic acid, ascorbic acid,
vitamin A,
vitamin D, vitamin E, vitamin K and derivatives thereof, calciferols,
mecobalamin, and the like. Also included within the term "vitamin" are the
coenzymes thereof, as coenzymes are generally beneficial agents for the body.
Coenzymes include thiamine pyrophosphates (TPP), flavin mononucleotides
(FMM), flavin adenine dinucleotides (FAD), Nicotinamide adenine dinucleotides
(AND), Nicotinamide adenine dinucleotide phosphate (NADP), Coenzyme-A
(CoA) pyridoxal phosphate, biocytin, tetrahydrofolic acid, coenzyme Biz,
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lipoyllysine, 1, 1-cis-retinal, and 1,2, 5-dihydroxycholecalciferol. The term
"vitamin" also includes choline, carnitine, and alpha, beta, and gamma
carotenes. Thus, a vitamin may include, for example, substances that may or
may not be required in the diet. Salts of vitamins are also suitable.
The term "mineral", as used herein, refers to inorganic substances,
such as metal compounds and the like, generally required in the diet. Thus,
suitable minerals include, without limitation, calcium, iron, zinc, selenium,
copper, iodine, magnesium, phosphorus, chromium and the like, their salts,
chelates, and other compositional forms and combinations thereof.
Other nutritional ingredients, commonly referred to as "dietary
supplements", include substances which have an appreciable nutritional effect
when administered in small amounts. Suitable dietary supplements include,
without limitation, ingredients such as bee pollen, bran, wheat germ, kelp,
cod
liver oil, ginseng, and fish oils, amino acids, proteins and mixtures thereof.
It
should be appreciated that dietary supplements may also incorporate vitamins
and minerals.
The medicament may be incorporated in each fiber. For example,
each fiber may be formed, such as by extrusion or other methods, with the
medicament. Alternatively, the medicament may be distributed on each fiber or
over a collection of fibers, in the composition. For example, individual
fibers or a
grouping of fibers may be coated with the medicament.
The amount of the medicament included in the formulation will
generally depend upon the particular medicament, its intended use, and patient
profile. The medicament is dosed in accordance with accepted pharmacy and
FDA practices and government regulations. For example, medicament
compositions targeted for administration to children will include the
medicament
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in smaller amounts such as from 1 mg to about 25 mg, which encompass
therapeutically effective doses for a majority of pediatric medicaments, and
generally sufficient dosages for many adult medications. Effective dosages are
generally that amount or quantity of a drug or pharmaceutically active
substance, which is sufficient to elicit the required or desired therapeutic
response (biological response) when administered to a patient. In one
embodiment, the composition includes the medicaments) in dosage amounts
of up to about 1000 mg. In another embodiment, the composition includes the
medicaments) in dosage amounts ranging from about 25 mg to about 100 mg.
In yet another embodiment, the composition includes the medicaments) in
dosage amounts of up to about 25 mg. Larger dosages will generally increase
the sire of the fibrous matrix. But this is not a disadvantage, as the
composition
may be dissolved, broken down and otherwise delivered in a suitable liquid or
aqueous medium of the patient's choice.
The amount of the medicament may also be dependent on the
amount of the collagen-based carrier, and vice versa, in the composition. For
example, depending upon physical properties and. degree of dispersion and
solubility in the oral environment desired, the quantities and weight ratios
of the
carrier to the medicament are varied. In one embodiment of the invention, the
carrier to medicament weight ratio in the composition, or in each fiber, is in
the
range from about 50:1 to about 1:50. In another embodiment, the carrier to
medicament weight ratio is in the range from about 10:1 to about 1:10. In yet
another embodiment, the carrier to medicament weight ratio is about 1:1.
With reference to a vitamin or mineral, an effective amount is
generally at least about 10% of the United States recommended Daily
Allowance ("RDA") of the particular ingredient for a patient. For example, an
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effective amount of vitamin C would include an amount of vitamin C sufficient
to
provide 10% or more of the RDA. Typically, where the formulation includes a
vitamin or mineral, it will incorporate higher amounts, such as about 100% or
more of the applicable RDA.
The composition as a whole, each fiber, or a selected collection of
fibers, may further include other desirable excipients. Excipients that
dissolve
in the oral environment are useful. Suitable excipients include, without
limitation, carbohydrates, mono-saccharides, di-saccharides, poly-saccharides
of simple sugars, sugar derivatives, and the like. Examples of suitable sugars
and other excipients include, without limitation, high caloric sugars such as
sucrose, lactose, glucose, d-glucose, I-glucose, maltose, dextrose, fructose,
fructosan, gentiobiose, cellobiose, panose, malto-triose, malto-tetrose,
arabinose, mannose, d-mannose, galactose, d-galactose, d-glyceraldehyde,
amylose, allose, altose, talose, gulose, idose, ribose, erythrose, threose,
lyxose, xylose, d-xylose, rhamnose, invert sugar, corn sugar, inositol,
glycerol,
glycogen, pectin, agar, sorbitol, mannitol and combinations thereof; low
caloric
sugars, such as sucralose, polyols, tagarose, trehalose, xylitol, dextrans,
dextrins, dextrates, polysorbates, maltodextrin, xylitol, amylase,
amylopectin,
ribose, f3-maltose, fucose, sialic acid (neuraminic acid), N-
acetylgalactosamine,
N-acetylglucosamine, sedoheptulose, ribulose, xylulose and combinations
thereof; non-sugar sweeteners, such as acesulfane potassium, aspartame,
neotame, saccharin, stevioside and combinations thereof; non-sweeteners,
such as alitame, cyclamate, dihydrchalcones (DHCs), glycyrrhizin, thaumatin,
gelatin, glycerin, triacetin, trehalose, alginates, gellan gum, cellulose,
microcrystalline cellulose, xanthan gum, cellulose acetate phthalate,
hydropropylcellulose, hydropropylmethylcellulose, ethylcellulose,
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methylcellulose, L-HPC (low-substituted hydroxypropyl cellulose), carrageenan,
croscarmellose, povidone, crospovidone, starch, sodium starch glycolate,
glucan, Adjumer~ (polyidi[carboxylatophenoxyl[phosphazene), Pleuran
(glycan), Pluronic L 121 (Poloxamer 401 ), glyceraldehydes, dihydroxyacetone
and combinations thereof; and combination carriers/floss/menstruum, such as
without being limited to, directly compressed dried honey (Hony-TAB~), lactose
and aspartame, lactose and cellulose, microcrystalline cellulose and
carrageenan, microcrystalline cellulose and guar gum, microcrystalline
cellulose
and sodium carboxymethylcellulose, microcrystalline cellulose and lactose, and
a sugar and starch combination.
Desirable adjuvants including, without limitation, binders, non-
effervescent disintegrants, coloring agents, flavors, taste enhancers, taste
maskers, oral dispersing agents, stabilizers, preservatives, diluents, filler,
compaction agents, bioadhesives, effervescent disintegration agents, and the
like, may also be included.
Examples of binders include acacia, tragacanth, gelatin, starch,
cellulose materials such as methyl cellulose and sodium carboxy methyl
cellulose, alginic acids and salts thereof, magnesium aluminum silicate,
polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars,
invert
sugars and the like. Binders may generally be used in an amount up to about
60% by weight and advantageously from about 10% to about 40% by weight of
the total composition.
Furthermore, one or more disintegrants or dispersion enhancers can
be used to enhance the breakability of the composition in an aqueous
environment, such as the oral cavity. Disintegrants include starches as corn
starch, potato starch and modified starches thereof, sweeteners, clays such as
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bentonite, micro-crystalline cellulose (even as high HLB emulsifier
surfactants),
purified wood cellulose, alginates, polyvinylpyrrolidones, gums such as agar,
guar, partially hydrolyzed guar gum, locust bean, karaya, kaolin, pecitin,
sodium
starch glycolate, isoamorphous silicate, and tragacanth. Disintegrants may
generally comprise up to about 20% by weight and advantageously between
about 2% and about 10% by weight of the final composition.
Coloring agents may include titanium dioxide, and dyes suitable for
food such as those known as F.D. & C. dyes and natural coloring agents such
as grape skin extract, beet red powder, beta-carotene, annato, carmine,
turmeric, paprika, etc. The amount of the coloring agents) used may range
from about 0.1 % to about 3.5% by weight of the final administrable
composition.
Flavors incorporated in the composition may be chosen from
synthetic flavor oils and flavoring aromatics and/or natural oils, extracts
from
plants, leaves, flowers, fruits and so forth and combinations thereof. These
may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay
oil,
anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage,
oil of
bitter almonds and cassia oil. Also useful as flavors are vanilla, citrus oil,
including lemon, orange, grape, lime and grapefruit, and fruit essences,
including apple pear, peach, strawberry, raspberry, cherry, plum, pineapple,
apricot and so forth. Flavors, which have been found to be particularly
useful,
include commercially available orange, grape, cherry and bubble gum flavors
and mixtures thereof. The amount of flavoring may depend on a number of
factors, including the organoleptic effect desired. Flavors may be present in
an
amount ranging from about 0.5% to about 3.0% by weight of the composition.
Commonly accepted flavors include grape and cherry flavors, and citrus flavors
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such as orange. It is also appreciated that inclusion of flavoring agents can
also influence the final flavor of the vehicle, furthering compliance with
ingestion
of the medicament.
In accordance with another aspect of the invention, a bioadhesive,
such as a bioadhesive polymer, generally increases the contact time between
the composition and the oral mucosa, particularly where the composition is
administered directly into the oral cavity and the dissolving medium is saliva
with the mucoadhesive properties, the inventive compositions are particularly
useful for difficult patients. Specifically, pediatric patients, noncompliant
patients and/or obstieperous patients are hindered or prevented from spitting
the composition out of their mouth. This provides more accurate dosing and
compliance with a desired dosing regimen. Non-limiting examples of known
bioadhesives, or mucoadhesives, include carbopol (various grades), sodium
carboxy methylcellulose, methylcellulose, polycarbophil (Noveon AA-1 ),
hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium alginate, and
sodium hyaluronate.
(n another aspect, one or more effervescent disintegration agents
might be used. Effervescent disintegration agents generally include at least
one
acid, such as citric acid, tartaric acid, malic aicd, fumaric acid, adipic
acid,
succinic acid, acid anhydrides, acid salts and mixtures thereof, and at least
one
base or a source of carbonate, such as from alkali-metal carbonate salts,
bicarbonate salts, and mixtures thereof. The reaction of the acid and base
produce gas or cause effervescence in the oral cavity or in the liquid used to
dissolve the composition prior to ingestion. With carbonate bases, carbon
dioxide gas is produced. The action of such an agent can often aid in masking
objectionable tastes of active pharmaceutical ingredients, vitamins, minerals,
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and other medicaments. Generally, the positive organoleptic sensation
achieved by the production of gas in the mouth, combined with the texture,
speed and sensation of resulting effervescence also generally masks
undesirable flavors in the mouth.
Where effervescent agents are included, they may be included in the
composition in various different ways. One method includes incorporating the
entire effervescent agent in the fibrous matrix used to form the composition.
Another manner of incorporating an effervescent disintegrating agent is to
include the entire agent as an additive, which is mixed with fibrous matrix
after
it is formed. Another method contemplates incorporating one portion of the
disintegrating agent in the fibrous matrix and another portion of the
disintegrating agent as an additive after formation of the fibrous
composition.
The components of the composition, i.e., the collagen-based carrier
and the medicaments) and other desired excipients, where incorporated into
the fiber, are processed or converted to fibrous, string-like, threads. Known
technology utilized to form the fibrous backbone of the composition is one of
creating threads or floss plus the active medicament. For example, the
components may be combined into threads or floss in an admixed fashion,
wherein the carrier and the medicament, plus other excipient(s) would also
need to be added such that any small or large portion of the finally
formulated
fibrous matrix, or any single portion of a thread or of a fiber, would contain
a
ratio of the above-mentioned ingredients in a desired proportion to the ratio
of
all of the ingredients of the composition. Such ratios will be formed as
desired
for the purpose of dose titration and to secure accurate and reproducible
dosing of the medicament-to a patient.
Known conventional methods of forming fibers and threads including
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extrusion, co-extrusion, gel casting, flash-drying and freeze-drying
techniques
may be employed. Many collagen materials are available commercially, or may
be extracted following well-recognized biochemical practices. A suitable
method for extraction and reconstitution from a source is disclosed in U.S.
Patent No. 6,197,934, which patent disclosure is incorporated herein by
reference in its entirety. Generally, the collagen is acid extracted, salt
extracted, or chemically and enzymatically solubilized and extracted in a
molecular or small aggregate state, from the raw material source. Such
extracts are typically stabilized in a mildly acidic solution and kept
refrigerated
for longer shelf life.
Reconstitution causes the collagen molecules or aggregates to self-
assemble into a fibrous structure, often resembling its original native state.
The
reconstitution (or self-assembly) process may be induced by titrating the
collagen solution to conditions approaching its physiological state (pH 7.0-
7.4
and 20-35°C in an ionically balanced phosphate buffer). Alternatively
collagen
may be made to precipitate by rapidly increasing the pH above 7.4 and
removing water from the solution, thereby increasing the concentration of
solids.
Prior to, during, or after reconstitution or precipitation, a desired and
compatible medicament, such as an API, is then added to the collagen. Then
the collagen may be subjected to a compression process wherein the
reconstituted collagen (RC)-medicament mixture is squeezed in one or more
layers, draining the liquid from the solution to result in a rapidly drying
solid
material. This solid is collected and molded into a desired form prior to
drying.
In the case that the RC and the medicament are incompatible in the
solution form, the layup process is performed sequentially with independent,
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preformed RC gels, semi-dried or dried collagen matrices and medicament
solutions, to form alternating layers of the RC and the medicament. With
reference to Figs. 3A-3F, there is shown an exemplary method of making a
composition 30 of the present invention. As shown, a thick viscous solution of
reconstituted collagen (RC) 40 is first poured onto a casting surface 42 of
suitable collection equipment and compression or squeeze member 46 is
pushed or otherwise moved across the RC 10 squeezing or compressing RC
into a thin layer 44 while forcing out most of the liquid portion of RC10
through drain 48. The surface 42 may be sufficiently designed and configured
10 for draining liquid to drain 48. As illustrated in Figure 3B, a thin layer
44 may
require that member 46 carry away excess RC 47. Next, an amount of a
medicament composition or solution 50 (e.g. API) is poured onto layer 44 to
form a second layer. The casting surface 42 is lowered vertically with layer
44
to provide a volume to capture the medicament 50 for forming the second layer
(See Figure 3C). Then, the second layer 52 is also compressed or squeezed
with member 46 to force liquid from medicament solution 50 through drain 48
thereby forming second layer 52 of a medicament, upon the first RC layer 44.
Again, as shown in Figure 3D, additional material 53 might be carried away.
Another layer 54 of RC is similarly formed to sandwich medicament layer 52
between layers 44 and 54, as shown in Figures 3E and 3F. Fig. 4 illustrates an
exploded view of the composition 60 formed by the method shown in Figs. 3A-
3F. Fig. 5 illustrates the final product composition formed with the multiple
layers together.
Another suitable method for preparing the fibrous composition in
accordance with the present invention is a printing process. With reference to
Fig. 6, there is shown an exemplary method of printing successive layers of RC
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followed by a medicament in a desired amount. As shown, a layer 70 of RC
may be printed with a protein printing head 72 and after the RC layer has
dried,
a layer 74 of a medicament may be printed on the layer 70 of the RC. Thus, in
this manner sequential layers 70 of RC, or specific areas of the RC layers)
70,
can be. printed over with the medicament material to form a sandwich type of
composition 76, as illustrated in Fig. 7, comprising two RC layers sandwiching
the medicament layer. This printing method allows one to uniformly distribute
and/or control the amount of the medicament on RC layer 70.
The printing process disclosed in Figure 6 may be used and
selectively controlled to vary the distribution and/or amount of the
medicament
in the product 76. For example, a greater amount of medicament might be
deposited in one location of layer 70, such as the center, then at another
location, such as the periphery. Furthermore, different API's might be used in
different areas of the product 6. For example, one API might be deposited in
one section, quadrant or one half of the product, while another different API
might be deposited on a different section, quadrant or half of the product.
The
final composition 76, as shown in Fig 7, can further be perforated, scored,
and/or marked, such as with lines 80, to indicate dosage, amounts and/or other
desired information.
Yet another suitable method of forming the fibers or threads is with
the process of extrusion, such as electrostatic extrusion. Extrusion may
generally be accomplished without spinning and/or melting any of the extruded
components. Two or more extruded streams of some or all of the components
of the composition may be converged and mixed to form threads or fibers
utilized in the composition. The extruded fibers or filaments may then be
formed in a spool or processed in multiple other ways. For example, the fibers
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may then be aligned into sheets. The sheets may be stacked one on top of the
other in layers. For example, each fiber in a sheet or layer may be oriented
in
one direction, i.e., horizontal or up and down, whereas fibers in another
sheet
may be oriented in a vertical nature, or generally perpendicular relative the
. orientation of fibers in the adjacent sheet(s). Stacking of layers may
involve
alternating horizontal and vertically oriented fiber sheets or successive
sheets
may either be all horizontally oriented fibers or all vertically oriented
fibers.
Other combinations such as to form woven and cross-woven layers of fibers or
threads, as appreciated by those skilled in the art, are also contemplated
herein.
By virtue of being fibrous, the composition may then be compressed
into desirable unique shapes. For example, the sheets may be compressed into
multi-layered "blankets", and them molded into desirable shapes, including
without limitation, a biconvex shape, a biconcave shape, a flattened shape,
and
the like. The particular orientation of layers will generally affect the
tensile
strength and/or the ability of the sheets or layered blanket to absorb liquid.
With reference to Fig.1, there is shown a top-down view of an
exemplary final shape of the fibrous composition. As shown, composition 10 is
circular in shape. Composition 10 includes a central area 14 and terminal or
peripheral areas 16,18. Central area 14 generally contains a concentration of
collagen-based fibers and medicament in a desired weight ratio. Composition
10 may be further perforated and/or marked as desired. For example, score
lines 21 divide composition 10 into quadrants.
With reference to Fig. 2, there is shown a side view of the exemplary
form of the composition illustrated in Fig.1. As shown, central area 14 is
elevated or raised relative to terminal or peripheral areas 16,18. Terminal
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areas 16,18 are more compressed and flattened. In that sense, the composition
takes on a fusiform shape.
The composition, once formed into desired shapes, could be further
processed utilizing kiss-cut technology to perforate or separate desired
amounts of the composition for dose titration and dose administrative purposes
in accordance with another aspect of the invention. Indented scoring of the
composition makes accurate tearing or cutting of the composition easier.
Accordingly, an individual dose may be easily and conveniently obtained by
simply cutting or severing scored sections of the composition. Alternatively,
layers, sheets or blankets of the fibrous composition may be made
commercially available and may be further processed to contain or "wrap" a
pill
or tablet.
The fibrous composition or matrix may be configured with an API that
is released immediately upon ingestion of the composition. Wrapped therein
may be a solid pill, tablet or other dosage form which is then ingested to
release its API in a more delayed fashion in the gut. The API's between the
fibrous composition and the other dosage form (e.g. pill/tablet) might be the
same or different. Furthermore, multiple API's might be incorporated into each
dosage form.
Each sheet and/or blanket of fibers may be "marked" to indicate the
nature and/or amount of the medicament, the dosage schedule, day indicia,
time indicia, and the like, as desired. The markings may also indicate the
content of each scored section of the composition. The ability to mark the
composition provides the advantage of allowing the manufacturer to be in
compliance with FDA regulations and other identification requirements. The
composition can be marked with FD&C approved food coloring or other GRAS
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items into halves, quarters, or other dose sizes. The quarter markings are
generally suitable for solid oral medications.
The present invention will be further appreciated in light of the
following example.
The following is an example of a fibrous, collagen-based, medicament-
containing composition of the present invention prepared by a gel-casting
method. Collagen in an acidic aqueous solution at 3 mg/ml is dialyzed in the
cold against a 32.7 mM phosphate buffer solution at a pH range from about 7.0
to 7.4. This solution is cast into molds and the temperature increased to
about
20°C -35°C. After a period of time, typically about several
minutes, the solution
changes in turbidity as the collagen begins to undergo molecular self-
assembly.
This process is called fibrillogenesis, or reconstitution, and is completed
when
all the free collagen molecules have become aggregated to one another. The
resulting aggregate is a high water content, gel matrix containing
consolidated
collagen fibrils, produced by a process generally referred to as thermal
gelation.
The fibril structure is normally formed in a random non-woven pattern, but may
be influenced by convection, shear flow or electro-magnetic fields to generate
oriented structures having unique properties, as disclosed in U.S. Patent No.
4,544,516, which disclosure is incorporated herein by reference in its
entirety.
Selected medicaments, such as an AP1, may be added to the
collagen solution prior to gelation, or they may be dialyzed or otherwise
infiltrated into the formed aqueous gels by known methods, prior to drying the
gel. The cast gels are then generally dried by freeze-drying or air-drying.
Freeze
drying provides a high surface area, porous collagen-based matrix suitable for
the oral medicament delivery system of the present invention. Portions of a
cast freeze-dried film or individually molded sections may be pressed,
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laminated or otherwise mechanically modified to form desired shapes for
administration to a patient.
The medicament may be added before or after the gel is shaped
to provide the final form of the composition administered in the oral
medicament delivery system of the invention. Shaping or lamination may be
facilitated by rewetting the dried matrix or by adding liquid collagen to the
matrix
and re-drying while molding the matrix to the desired shape.
By virtue of the foregoing, the present invention provides a
medication delivery system for orally administering a medicament to a patient.
The invention takes advantage of the desirable properties of collagen protein,
which have been previously utilized in a variety of useful medical
applications,
while addressing weaknesses of traditional oral delivery methods. More
specifically, the invention provides a composition constructed from a matrix
of
collagen or collagen-based fibers carrying one or more medicaments, and
assembled in such a way as to disperse or dissolve on presentation to the
buccal mucous membrane of the oral cavity. As such, the invention overcomes
difficulties with traditional methods of oral administration, such as those
involving swallowing of a pill, tablet, capsule, or other solid dosage form.
The
fibrous, collagen-based composition is flexible, readily soluble in the oral
environment, and may be additionally appealing with sweeteners, shape,
colors, taste enhancers, taste maskers, and the like, to render it more
appealing for ingestion to both children and adults. Dose titration of the
composition is possible by its physical structure and characteristics.
Specifically, doses may be titrated by administering segmented portions of the
fibrous matrix composition by simply cutting them with a pair of scissors or a
knife.
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Further, addition of a low dose liquid medication onto and into the
composition may create a single unit swallowed medication. Particularly, forms
of the composition having larger centers that are less compacted generally
contain more space or air between fibers or individual filaments thereby
allowing for absorption of the liquid. In that sense, the composition acts as
a
sponge to absorb and hold the liquid medication. The liquid might include the
same API as an API incorporated into the fibrous matrix. Alternatively, it may
be
different. Still further, the liquid medication might be the only API in the
overall
product.
Another advantage is that the composition, by virtue of its flexible
fibrous matrices, has the ability to "wrap around" another dry medication,
such
as a pill or powder, to create a single unit swallowed medication. Molding of
the composition into desirable forms, as well as having self-adhering
properties
by virtue of other desired excipients therein along the edges of the
composition,
also allows for the composition of a single unit swallowed medication. Thus,
the
present invention enhances ingestion of a medicament dose and, therefore,
improves patient compliance with ingestion in accordance with a medication
regimen.
White the present invention has been illustrated by the description of
embodiments thereof, and while the embodiments have been described in
considerable detail, it is not intended to restrict or in any way limit the
scope of
the appended claims to such detail. Additional advantages and modifications
will be readily apparent to those skilled in the art. The invention in its
broader
aspects is, therefore, not limited to the specific details, representative
apparatus, method, and examples described. Accordingly, departures may be
made from such details without departing from the scope or spirit of
Applicant's
34
CA 02550374 2006-06-16
WO 2005/063217 PCT/US2004/042814
general inventive concept.
WHAT IS CLAIMED IS:
